Prodrug derivatives of carboxylic acid drugs

ABSTRACT

##STR1## 
     Novel ester derivatives of carboxylic acid medicaments of formula (I), wherein R--COO--represents the acyloxy residue of a carboxylic acid drug or medicament, n is an integrer from 1 to 3, and R 1  and R 2  are the same or different and are selected from a group consisting of an alkyl, an alkenyl, an aryl, an aralkyl, a cycloalkyl and which group may be unsubstituted or substituted, or R 1  and R 2  together with the N forms a 4-, 5-, 6- or 7-membered heterocyclic ring, which in addition to the nitrogen atom may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and which heterocyclic group may be substituted. These compounds are highly biolabile prodrug forms of the corresponding carboxylic acid compounds and are highly susceptible to undergoing enzymatic hydrolysis in vivo whereas they are highly stable in aqueous solution. The novel derivatives are less irritating to mucosa than the parent carboxylic acids and may provide an improved bio-availability of the drugs.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel highly biolabile prodrug forms ofdrugs containing one or more carboxylic acid functions, to methods forpreparing the prodrug forms, to pharmaceutical compositions containingsuch prodrug forms, and to methods for using the prodrug forms.

For purposes of this specification, the term "prodrug" denotes aderivative of a known and proven carboxylic acid functional drug (e.g.naproxen, L-dopa, salicylic acid, etc.) which derivative, whenadministered to warm-blooded animals, e.g. humans, is converted into theproven drug. The enzymatic and/or chemical hydrolytic cleavage of thecompounds of the present invention occurs in such a manner that theproven drug form (parent carboxylic acid drug) is released, and themoiety or moieties split off remain nontoxic or are metabolized so thatnontoxic metabolic products are produced.

These novel prodrug forms are esters of certain hydroxy-amides. Theseesters combine a high susceptibility to undergo enzymatic hydrolysis invivo with a high stability in aqueous solution. The new ester prodrugtype is further characterized by providing ample possibilities forvarying the aqueous solubility as well as the lipophilicity of theprodrug derivatives with retainment of a favourableenzymatic/non-enzymatic hydrolysis index.

2. Description of the Prior Art

It is well-known that a wide variety of compounds containing carboxylicacid functions are biologically active. For example, such structure ischaracteristic of non-steroidal anti-inflammatory agents such asnaproxen, ibuprofen, indomethacin and the like; penicillin andcephalosporin antibiotics such as ampicillin, cefmetazole and the like;as well as other compounds having diverse biological properties andstructures.

It is also well-known that such prior art compounds are characterized bycertain inherent disadvantages, notably bioavailability problems uponadministration via oral, rectal or topical routes. The unionized form ofa drug is usually absorbed more efficiently than its ionic species andas the carboxylic acid functional group is significantly ionized atphysiological pH, the result is that carboxylic acid agents are poorlyabsorbed through lipid-water membrane barriers. In addition, bysuffering from reduced bioavailability, some acidic drugs, notablynon-steroidal anti-inflammatory agents (ibuprofen, tolmetin, naproxen,indomethacin, etc.), are irritating to the mucous membrane of thegastro-intestinal tract.

A promising approach to solve such problems may be esterification of thecarboxylic acid function to produce lipophilic and non-irritatingprodrug forms, provided that the biologically active parent drug can bereleased from the prodrug form at its sites of activity. However,several aliphatic or aromatic esters of carboxylic acid drugs are notsufficiently labile in vivo to ensure a sufficiently high rate andextent of prodrug conversion. For example, simple alkyl and aryl estersof penicillins are not hydrolyzed to active free penicillin acid in vivo(Holysz & Stavely, 1950) and therefore have no therapeutic potential(Ferres, 1983). Similarly, the much reduced anti-inflammatory activityobserved for the methyl or ethyl esters of naproxen (Harrison et al.,1970) and fenbufen (Child et al., 1977) relative to the free acids maybe ascribed to the resistance of the esters to be hydrolyzed in vivo. Inthe field of angiotensin-converting enzyme inhibitors ethyl esters havebeen developed as prodrugs for the parent active carboxylic acid drugsin order to improve their oral bioavailability. Enalapril is such aclinically used ethyl ester prodrug of enalaprilic acid. Plasma enzymesdo not hydrolyze the ester and the necessary conversion of the ester tothe free acid predominantly takes place in the liver (Tocco et al.,1982; Larmour et al., 1985). As recently suggested (Larmour et al.,1985), liver function may thus be a very important determinant for thebioactivation of enalapril and hence its therapeutic effect. The limitedsusceptibility of enalapril to undergo enzymatic hydrolysis in vivo hasbeen shown to result in incomplete availability of the active parentacid (Todd & Heel, 1986). Pentopril is another ethyl ester prodrug of anangiotensin-converting enzyme inhibitor which also is highly stable inhuman plasma. In this case less than 50% of an oral dose of the prodrugester appears to be deesterified in vivo to the active parent acid(Rakhit & Tipnis, 1985).

As has been demonstrated in the case of penicillins (Ferres, 1983) theseshortcomings of some ester prodrugs may be overcome by preparing adouble ester type, acyloxyalkyl or alkoxycarbonyloxyalkyl esters, whichin general show a higher enzymatic lability than simple alkyl esters.The general utility of this double ester concept in prodrug design is,however, limited by the poor water solubility of the esters of severaldrugs and the limited stability of the esters in vitro. In addition,such esters are oils in many cases, thus creating pharmaceuticalformulation problems.

In view of the foregoing, it is quite obvious that a clear need existsfor new ester prodrug types possessing a high susceptibility to undergoenzymatic hydrolysis in plasma or blood and further more beingcharacterized by providing ample possibilities for varying orcontrolling the water and lipid solubilities.

In accordance with the present invention it has now been discovered thatesters of the formula I below are surprisingly rapidly cleavedenzymatically in vivo, e.g. by plasma enzymes, and fulfil theabove-discussed desirable attributes.

A few compounds related to certain compounds of formula I have beenreported in the literature. Thus, Boltze et al. (1980) have describedvarious N-unsubstituted and N-monosubstituted2-[1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetyloxy]-acetamidederivatives having anti-inflammatory properties. Similarly, someacetamide derivatives of flufenamic acid have been reported by Boltze &Kreisfeld (1977). 2-[2-(Acetyloxy)benzoyloxy]-acetamide and otherrelated ester derivatives of acetylsalicylic acid are disclosed in Ger.Offen. 2,320,945.

However, there is no suggestion that the compounds described have anyprodrug activity, and enzymatic hydrolysis of the compounds into theparent carboxylic acid drugs is neither explicitly nor implicitlymentioned.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a novel esterprodrug type characterized by possessing a high susceptibility toundergo enzymatic hydrolysis in vivo and at the same time providingample possibilities for varying the water and lipid solubilities of thederivatives.

It is another object of the present invention to provide novelbioreversible derivatives for drugs or biologically active agents havinga carboxylic acid function which derivatives, when administered towarm-blooded animals, e.g. humans, elicit thebio-affecting/pharmacological response characteristic of the acids fromwhich they are derived, yet which are characterized in being lessirritating to topical and gastric or intestinal mucosal membranes.

It is another object of this invention to provide prodrugs of carboxylicacid agents which are capable of providing increased biomembranetransport so that the parent drugs are more bioavailable from the siteof administration such as the gastro-intestinal tract, the rectum, theskin or the eye of the human body.

It is a further object of the present invention to provide suchderivatives of conventional carboxylic acids which are prodrugs designedto cleave in such a manner as to enable the original parent drug form tobe released at its therapeutic site or sites of activity, while theremaining cleaved moiety is non-toxic and/or is metabolized in anontoxic fashion.

It is still another object of this invention to provide prodrugcompounds which utilize hydrolytic enzymes to generate the parentcarboxylic acid-type drug from the prodrug form.

It is yet another object of the present invention to provide derivativesof carboxylic acid agents which derivatives are "soft" in nature, i.e.,which are characterized by in vivo destruction to essentially non-toxicmoieties, after they have achieved their desired therapeutic role (forexample, the compounds derived from steroidal acids of formula IIbelow).

Other objects, features and advantages of the invention will be apparentto those skilled in the art from the detailed description of theinvention which follows.

The foregoing objects, features and advantages are provided by the novelcompounds of the formula I ##STR2## wherein R--COO-- represents theacyloxy residue of a carboxylic acid drug or medicament,

n is an integer from 1 to 3, and

R₁ and R₂ are the same or different and are selected from a groupconsisting of an alkyl group, an alkenyl group, an aryl group, anaralkyl group, a cycloalkyl group, in which the alkyl, alkenyl, aryl,aralkyl or cycloalkyl group is unsubstituted or substituted with one ormore substituents selected from:

a halogen atom,

a hydroxy group,

a carbonyl group,

a straight or branched-chain alkoxy group having the formula R₃ --O--,wherein R₃ represents an alkyl group or an aryl group, which groups maybe unsubstituted or substituted with one or more of a halogen atom or ahydroxy group,

a carbamoyl group having the formula ##STR3## wherein R₄ and R₅ are thesame or different and are hydrogen, an alkyl group or are selected froma group having the formula --CH₂ NR₇ R₆, wherein R₆ and R₇ are the sameor different and are hydrogen, an alkyl group, or together with theadjacent nitrogen atom form a 4-, 5-, 6- or 7-membered heterocyclicring, which in addition to the nitrogen may contain one or two furtherheteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur,

an amino group having the formula --NR₈ R₉, wherein R₈ and R₉ are thesame or different and are hydrogen, an alkyl group or together with theadjacent nitrogen atom form a 4-, 5-, 6- or 7-membered heterocyclicring, which in addition to the nitrogen may contain one or two furtherheteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur,

an acyloxy group having the formula --COOR₁₀, wherein R₁₀ is an alkyl,aryl or aralkyl group,

an oxyacyl group having the formula R₁₁ COO-- wherein R₁₁ is hydrogen,an alkyl group, an aryl group, an aralkyl group, a cycloalkyl group, inwhich the alkyl, aryl, aralkyl or cycloalkyl group is unsubstituted orsubstituted with one or more of halogen atom, a hydroxy group, an alkoxygroup of the formula R₃ --O-- as defined above, a carbamoyl group of theformula --CONR₄ R₅ as defined above or an amino group having the formula--NR₈ R₉ as defined above;

or R₁ and R₂ are combined so that --NR₁ R₂ forms a 4-, 5-, 6- or7-membered heterocyclic ring, which in addition to the nitrogen atom maycontain one or two further heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur, and which heterocyclic ringmay be substituted with a hydroxy group, a carbonyl group, an alkylgroup or an oxyacyl group having the formula R₁₁ COO--, wherein R₁₁ isas defined above, or an acyloxy group having the formula --COOR₁₀,wherein R₁₀ is as defined above;

and nontoxic pharmaceutically acceptable acid addition salts thereof,with the proviso that if R₁ =alkyl then R₂ =alkyl, and if R₁ =CH₂ CH₂ OHthen R₂ =CH₂ CH₂ OH.

In the present context, the term "alkyl" designates C₁₋₈ alkyl which maybe straight or branched, such as methyl, ethyl, propyl, isopropyl,butyl, tert-butyl, pentyl, hexyl, heptyl, or octyl. The term "alkenyl"designates a C₂₋₆ -monounsaturated aliphatic hydrocarbon group which maybe straight or branched, such as propenyl, butenyl or pentenyl. The term"aryl" encompasses aryl radicals such as phenyl and naphthyl and alsothe corresponding aryl radicals containing one or more substitutents,which may be the same or different, such as alkylthio, alkyl, halogen,alkoxy, nitro, alkanoyl, carbalkoxy, dialkylamino, alkanoyloxy orhydroxy groups. The term "cycloalkyl" designates a radical containing 4to 7 carbon atoms, e.g. cyclohexyl. The term "aralkyl" designates aradical of the type -alkylene-aryl, wherein aryl is as defined above andthe alkylene moiety contains 1 to 6 carbon atoms and can be straight orbranched-chain, e.g. methylene, 1,2-butylene, and the like. When R₁ andR₂ in the formula I, R₄ and R₅ in the formula --CONR₄ R₅ and R₈ and R₉in the formula --NR₈ R₉ together with the adjacent nitrogen atom form a4-, 5-, 6- or 7-membered heterocyclic ring which in addition to thenitrogen atom may contain 1 or 2 further hetero atoms selected from thegroup consisting of nitrogen, oxygen, and sulfur, it may, for instance,be 1-piperidinyl, 1-pyrrolidinyl, 1-piperazinyl, 4-methyl 1-piperazinyl,hexamethyleneimino, morpholinyl, thiomorpholinyl, 1-pyrazolyl and1-imidazolyl.

When one or more asymmetric carbon atoms are present in the R₁ or R₂groups as defined above, it is understood that the present inventionalso encompasses all diastereomers or enantiomers, or mixtures thereof.Examples of isomers are D-, L-, and DL- forms.

The term "non-toxic pharmaceutically acceptable acid addition salts" asused herein generally includes the non-toxic acid addition salts ofcompounds of formula I, formed with non-toxic inorganic or organicacids. For example, the salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulphuric, sulphamic, nitric,phosphoric and the like; and the salts with organic acids such asacetic, propionic, succinic, fumaric, maleic, tartaric, citric,glycolic, lactic, stearic, malic, pamoic, ascorbic, phenylacetic,benzoic, glutamic, salicylic, sulphuric, sulphanilic, and the like.

As stated above, R--COO-- in formula I can represent the acyloxy residueof any drug, pharmaceutical or medicament (R--COOH) having one or morecarboxylic acid functions. The chemical structure of the carboxylic acidagents is not critical. Examples of drugs or pharmaceuticals from whichthe instant prodrugs are derived include but are not limited to:

a. Non-steroidal anti-inflammatory agents like:

1 Acetylsalicylic acid (aspirin)

2. Salicylic acid

3. Sulindac

4. Indomethacin

5. Naproxen

6. Fenoprofen

7. Ibuprofen

8. Ketoprofen

9. Indoprofen

10. Furobufen

11. Diflunisal

12. Tolmetin

13. Flurbiprofen

14. Diclofenac

15. Mefenamic acid

16. Flufenamic acid

17. Meclofenamic acid

18. Fenclozic acid

19. Alclofenac

20. Bucloxic acid

21. Suprofen

22. Fluprofen

23. Cinchophen

24. Pirprofen

25. Oxoprozin

26. Cinmetacin

27. Acemetacin

28. Ketorolac

29. Clometacin

30. Ibufenac

31. Tolfenamic acid

32. Fenclofenac

33. Prodolic acid

34. Clonixin

35. Flutiazin

36. Flufenisal

37. Salicylsalicylic acid

38. O-(Carbamoylphenoxy)acetic acid

39. Zomepirac

40. Nifluminic acid

41. Lonazolac

42. Fenbufen

43. Carprofen

44. Tiaprofenic acid

45. Loxoprofen

46. Etodolac

47. Alminoprofen

48. 2-(8-Methyl-10,11-dihydro-11-oxodibenz[b,f]oxepin-2-yl)-propionicacid

49. 4-Biphenylacetic acid

b. Cephalosporin antibiotics like:

100. Cephalothin

101. Cephacetrile

102. Cephapirin

103. Cephaloridine

104. Cefazolin

105. Cefazuflur

106. Ceforanide

107. Cefazedone

108. Ceftezole

109. Cephanone

110. Cefotiam

111. Cefamandole

112. Cefonicid

113. Cefuroxime

114. Cefoperazone

115. Cefpiramide

116. Cefpimizole

117. Cefsulodin

118. Cefoxitin

119. Cefmetazole

120. Cefotetan

121. Cefbuperazone

122. Cefotaxime

123. Cefmenoxime

124. Ceftizoxime

125. Cefpirome

126. Ceftazidime

127. Cefodizime

128. Ceftriaxone

129. Latamoxef

130. Cephalexin

131. Cephradine

132. Cefaclor

133. Cefadroxil

134. Cefatrizine

135. Cefroxadine

136. Cephaloglycin

c. Penicillin antibiotics like:

200. Benzylpenicillin

201. Phenoxymethylpenicillin

202. Phenethicillin

203. Methicillin

204. Nafcillin

205. Oxacillin

206. Cloxacillin

207. Dicloxacillin

208. Flucloxacillin

209. Azidocillin

210. Ampicillin

211. Amoxycillin

212. Epicillin

213. Cyclacillin

214. Carbenicillin

215. Ticarcillin

216. Sulbenicillin

217. Azlocillin

218. Mezlocillin

219. Piperazillin

220. Apalcillin

221. Temocillin

222. Carfecillin

223. Carindacillin

224. Hetacillin

d. 4-Quinolone antibiotics like:

300. Ciprofloxacin

301. Norfloxacin

302. Acrosoxacin

303. Pipemidic acid

304. Nalidixic acid

305. Enoxacin

306. Ofloxacin

307. Oxolinic acid

308. Flumequine

309. Cinoxacin

310. Piromidic acid

311. Pefloxacin

e. Steroidal monocarboxylic acids having the structural formula II:##STR4## H wherein R₂₀ is hydrogen, fluoro, chloro, or methyl; R₂₁ ishydrogen. fluoro or chloro; R₂₂ is hydrogen, methyl, hydroxy or --OCOR₂₄wherein R₂₄ is C₁ -C₇ straight or branched alkyl or phenyl; R₂₃ ishydrogen, hydroxy, or --OCOR₂₄ wherein R₂₄ is as defined above, with theproviso that when R₂₂ is hydroxy or --OCOR₂₄ and R₂₃ is other thanhydrogen, then R₂₂ and R₂₃ are identical; or R₂₂ and R₂₃ are combined toform a divalent radical of the type ##STR5## wherein R₂₅ and R₂₆, whichcan be the same or different are each C₁₋₇ straight or branched alkyl orphenyl; Z is carbonyl or β-hydroxymethylene; the wavy line at the16-position indicates the α or β-configuration; and the dotted line inthe ring A indicates that the 1,2-linkage is saturated or unsaturated.

A particularly preferred group of carboxylic acids of the formula IIconsists of the compounds wherein the structural variables representedby R₂₀, R₂₁, R₂₂, R₂₃ and Z and the dotted and wavy lines are identicalto those of a known anti-inflammatory steroid selected from the groupconsisting of hydrocortisone, betamethasone, dexamethasone,prednisolone, triamcinolone, fluocortolone, cortisone, fludrocortisone,chloroprednisone, flumethasone, fluprednisolone, meprednisone, methylprednisolone, paramethasone, prednison, flurandrenolone acetonide,amcinafal, amcinafide, clocortolone, desonide, desoximetasone,fifluprednate, flunisolide, fluocinolone acetonide. triamcinoloneacetonide, betamethasone 17-benzoate and betamethasone 17-valerate.Another preferred group of compounds of formula II consists of thecompounds wherein the structural variables represented by R₂₀, R₂₁, R₂₂,Z and the dotted and wavy lines are identical to those of a knownanti-inflammatory steroid selected from the group consisting ofhydrocortisone, cortisone, fludrocortisone, betamethasone,chloroprednisone, dexamethasone, flumethasone, fluprednisolone,meprednisone, methyl prednisolone, paramethasone and prednisolone, andR₂₃ is --OCOR₂₄ wherein R₂₄ is as hereinbefore defined, most especiallywhen R₂₄ is CH₃, C₂ H₅, C₃ H₇ or phenyl. Yet another preferred group ofparent acids of formula II consists of the compounds wherein thestructural variables represented by R₂₀, R₂₁, Z and the wavy and dottedlines are identical to those of triamcinolone, and R₂₂ and R₂₃ areidentical --OCOR₂₄ groupings wherein R₂₄ is as hereinbefore defined,most especially when R₂₄ is CH₃, C₂ H₅, C₃ H₇ or phenyl. Particularlypreferred parent acids encompassed by formula II include

6α-fluoro-11β-hydroxy-16α-methyl-3,20-dioxopregna-1,4-dien-21-oic acid;

9α-fluoro-11β,17α-dihydroxy-16β-methyl-3,20-dioxopregna-1,4-dien-21-oicacid;

9α-fluoro-11β,17α-dihydroxy-16α-methyl-3,20-dioxopregna-1,4-dien-21-oicacid;

11β,17α-dihydroxy-3,20-dioxopregn-4-en-21-oic acid;

9α-fluoro-11β,16α,17α-trihydroxy-3,20-dioxopregna-1,4-dien-21-oic acid;and

11β,17α-dihydroxy-3,20-dioxopregna-1,4-dien-21-oic acid;

as well as the corresponding 17-esters of the specific 17-hydroxycompounds just named, most especially the 17-propionates, butyrates andbenzoates thereof.

f. Prostaglandins like:

500. Prostaglandin E₂

501. Prostaglandin F₂α

502. 15-Deoxy-16-hydroxy-16-vinylprostaglandin E₂

503. 11-Deoxy-11.sub.α,12.sub.α -methanoprostaglandin E₂

504. 11-Deoxy-11.sub.α,12.sub.α -difluoromethanoprostaglandin E₂

405. Prostacyclin

506. Epoprostenol

507. dl-16-Deoxy-16-hydroxy-16 (α/β)-vinyl prostaglandin E₂

508. Prostaglandin E₁

509. Thromboxane A₂

510. 16,16-Dimethylprostaglandin E₂

511. (15R) 15-Methylprostaglandin E₂ (Arbaprostil)

512. Meteneprost

513. Nileprost

514. Ciprostene

g. Angiotensin-converting enzyme inhibitors like:

600. (2R,4R)-2-(2-Hydroxyphenyl)3-(3-mercaptopropionyl)-4-thiazolidinecarboxylicacid

601. Enalaprilic acid(N-[1-(S)-carboxy-3-phenyl-propyl]-L-alanyl-L-proline)

602. Captopril

603.N-Cyclopentyl-N-[3-[(2,2-dimethyl-1-oxopropyl)thio]-2-methyl-1-oxopropyl]glycine

604.1[4-Carboxy-2-methyl-2R,4R-pentanoyl]-2,3-dihydro-2S-indole-2-carboxylicacid

605. Alecapril(1-[(S)-3-Acetylthio-2-methyl-propanoyl]-L-propyl-L-phenylalanine)

606.[3S-[2[R*(R*)]],3R*]-2-[2-[[1-carboxy-3-phenylpropyl]-amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid

607. [2S-[1[R*(R*)]],2α,3αβ,7αβ]-1[2-[[1-carboxy-3-phenylpropyl]-amino]-1-oxopropyl]octahydro-1H-indole-2-carboxylicacid.

608. (S)-Benzamido-4-oxo-6-phenylhexanoyl-2-carboxy-pyrrolidine

609. Lisinopril

610. Tiopronin

611. Pivopril

h. Various other bio-affecting carboxylic acid agents:

700. Ethacrynic acid

701. L-Tyrosine

702. α-Methyl-L-tyrosine

703. Penicillamine

704. Probenicid

705. 5-Aminosalicylic acid

706. 4-Aminobenzoic acid

707. Methyldopa

708. L-Dopa

709. Carbidopa

710. Valproic acid

711. 4-Aminobutyric acid

712. Moxalactam

713. Clavulanic acid

714. Tranexamic acid

715. Furosemide

716. 7-Theophylline acetic acid

717. Clofibric acid

718. Thienamycin

719. N-Formimidoylthienamycin

720. Amphotericin B

721. Nicotinic acid

722. Methotrexate

723. L-Thyroxine

724. Cromoglycic acid

725. Bumetanide

726. Folic acid

727. Chlorambucil

728. Melphalan

729. Fusidic acid

730. 4-Aminosalicylic acid

731. Liothyronine

732. Tretinoin

733. o-Thymotinic acid

734. 6-Aminocaproic acid

735. L-Cysteine

736. Tranilast (N-(3',4'-dimethoxycinnamoyl)anthranilic acid)

737. Baclofen

738. 4-Amino-5-ethyl-3-thiophenecarboxylic acid

739.N-Cyclopentyl-N-[3-[(2,2-dimethyl-1-oxopropyl)thio]2-methyl-1-oxopropyl]glycine

740. Isoguvacine

741. Nipecotic acid

742. D-Eritadenine [(2R,3R)-4-adenin-9-yl-2,3-dihydroxybutanoic acid]

743. (RS)-3-Adenin-9-yl-2-hydroxypropanoic acid

744.1-[4-Carboxy-2-methyl-2R,4R-pentanoyl]-2,3-dihydro-2S-indole-2-carboxylicacid

745. Phenylalanylalanine

746. Glafenic acid

747. Floctafenic acid

748. N-(Phosphonoacetyl)-L-aspartic acid (PALA)

749. Proxicromil

750. Cysteamine

751. N-Acetylcysteine

752. Proglumide

753. Aztreonam

754. Mecillinam

755. All-trans-retinoic acid

756. 13-cis-retinoic acid

757. Isonipecotic acid

758. Anthracene-9-carboxylic acid

759. α-Fluoromethylhistidine

760. 6-Amino-2-mercapto-5-methylpyrimidine-4-carboxylic acid

761. Glutathione

762. Acivicin

763. L-α-Glutamyl dopamine

764. 6-Aminonicotinic acid

765. Loflazepate

766. 6-[[1(S)-[3(S),4-dihydro-8-hydroxy-1-oxo-1H-2-benzopyran-3-yl]-3-methylbutyl]amino]-4-(S),5(S)-dihydroxy-6-oxo-3(S)-ammoniohexanoate

767. Z-2-Isovaleramidobut-2-enoic acid

768. D,L-2,4-Dihydroxyphenylalanine

769. L-2-Oxothiazolidine-4-carboxylic acid

770. Iopanoic acid

771. 4-Aminomethylbenzoic acid

772. 4-Hydroxybenzoic acid

773. 4-Hydroxybutyric acid

774. Ticrynafen

775. 4-amino-3-phenylbutyric acid

776. 4-(Dimethylamino)benzoic acid

777. Capobenic acid

778. Pantothenic acid

779. Folinic acid

780. Orotic acid

781. Biotin

782. Mycophenolic acid

783. Thioctic acid

784. Pyroglutamic acid

785. Oleic acid

786. Linoleic acid

787. Cholic acid

788. Naturally occurring amino acids (e.g. glycine, histidine,phenylalanine and glutamic acid)

789. N,N-Dimethylglycine

790. Salazosulfapyridine

791. Azodisal

792. lsotretinoin

793. Etretinic acid

All of the above compounds are known in the art in the acid or saltform.

While all of the compounds encompassed by formula 1 essentially satisfythe objectives of the present invention, preferred compounds includethose derived from the following compounds (compounds A)

1. Acetylsalicylic acid

2. Salicylic acid

3. Sulindac

4. Indomethacin

5. Naproxen

7. Ibuprofen

8. Ketoprofen

11. Diflunisal

12. Tolmetin

13. Flurbiprofen

15. Mefenamic acid

21. Suprofen

31. Tolfenamic acid

119. CefmerazoIe

104. Gefazolin

130. Cephalexin

132. Cefaclor

133. Cefuroxime

134. Cefamandole

118. Cefoxitin

200. Benzylpenicillin

201. Phenoxymethylpenicillin

210. Ampicillin

211. Amoxycillin

214. Carbenicillin

217. Azlocillin

219. Piperacillin

6α-Fluoro-11β-hydroxy-16α-methyl-3,20-dioxopregna-1,4-dien-21-oic acid

9α-Fluoro-11β,17α-dihydroxy-16β-methyl-3,20-dioxopregna-1,4-dien-21-oicacid

9α-Fluoro-11β,17α-dihydroxy-16α-methyl-3,20-dioxopregna-1,4-dien-21-oicacid

11β, 17α-Dihydroxy-3,20-dioxopregn-4-en-21-oic acid

9α-Fluoro-11β,16α,17α-trihydroxy-3,20-dioxopregna-4-dien-21-oic acid

11β,17α-Dihydroxy-3,20-dioxopregna-1,4-dien-21-oic acid.

500. Prostaglandin E₂

501. Prostaglandin F₂α

508. Prostaglandin E₁

505. Prostacyclin

511. (15R)-15-Methylprostaglandin E₂ (Arbaprostil)

513. Nileprost

514. Ciprostene

601. Enalaprilic acid

602. Captopril

603.N-Cyclopentyl-N-[3[(2,2-dimethyl-1-oxopropyl)thio]-2-methyl-1-oxopropyl]glycine

604.1-[4-Carboxy-2-methyl-2R,4R-pentanoyl]-2,3-dihydro-2S-indole-2-carboxylicacid

607. [2S[1[R*(R*)]],2α,3αβ,7αβ]-1-[2-[[1-carboxy-3-phenylpropyl]amino]-1-oxopropyl]octahydro-1H-indole-2-carboxylcacid

705. 5-Aminosalicylic acid

707. Methyldopa

708. L-Dopa

710. Valproic acid

714. Tranexamic acid

715. Furosemide

722. Methotrexate

727. Chlorambucil

717. Clofibric acid

720. Amphotericin B

734. 6-Aminocaproic acid

754. Mecillinam

732. Tretinoin

771. 4-Aminomethylbenzoic acid

782. Mycophenolic acid

768. D,L-2,4-Dihydroxyphenylalanine

Particularly preferred compounds of the invention include those whereinR--COO is derived from one of the specific bio-affecting acids namedabove, n is 1 and R₁ and R₂ are as defined in connection with thegeneral formula I.

In especially preferred compounds of the formula I, R--COO is derivedfrom one of the compounds A above, n=1, and

R₁ =CH₃ or C₂ H₅, ##STR6##

It will be appreciated that in the especially preferred compoundsdefined immediately above, each and every possible combination betweenthe given examples of R₁ and R₂ in the derivative group --CH₂ CONR₁ R₂may, of course, be combined with each and every group R--COO derivedfrom the compounds A listed above, and that the above definition isequivalent to listing each and every possible combination of the listedexamples of R--COO, R₁ and R₂.

The invention further concerns compounds of the general formula I asdefined above wherein R₁ and R₂ both are alkyl or both are --CH₂ CH₂ OH,and

R--COO-- is the acyloxy residue of one of the following bio-affectingcarboxylic acid agents (compounds B)

2. Salicylic acid

3. Sulindac

4. Indomethacin

5. Naproxen

7. Ibuprofen

8. Ketoprofen

11. Diflunisal

12. Tolmetin

13. Flurbiprofen

15. Mefenamic acid

21. Suprofen

31. Tolfenamic acid

119. Cefmetazole

104. Cefazolin

130. Cephalexin

132. Cefaclor

133. Cefuroxime

134. Cefamandole

118. Cefoxitin

200. Benzylpenicillin

201. Phenoxymethylpenicillin

210. Ampicillin

211. Amoxycillin

214. Carbenicillin

217. Azlocillin

219. Piperacillin

6α-Fluoro-11β-hydroxy-16α-methyl-3,20-dioxopregna-1,4-dien-21-oic acid

9α-Fluoro-11β,17α-dihydroxy-16β-methyl-3,20-dioxopregna-1,4-dien-21-oicacid

9α-Fluoro-11β,17α-dihydroxy-16α-methyl-3,20-dioxopregna-1,4-dien-21-oicacid

11β,17α-Dihydroxy-3,20-dioxopregn-4-en-21-oic acid

9α-Fluoro-11β,16α,17α-trihydroxy-3.20-dioxopregna-4-dien-21-oic acid

11β,17α-Dihydroxy-3,20-dioxopregna-1,4-dien-21-oic acid.

500. Prostaglandin E₂

501. Prostaglandin F₂α

508. Prostaglandin E₁

505. Prostacyclin

511. (15R)15-Methylprostaglandin E₂ (Arbaprostil)

513. Nileprost

514. Ciprostene

601. Enalaprilic acid

602. Captopril

603.N-Cyclopentyl-N-[3-[(2,2-dimethyl-1-oxopropyl)thio]-2-methyl-1-oxopropyl]glycine

604.1-[4-Carboxy-2-methyl-2R,4R-pentanoyl]-2,3-dihydro-2S-indole-2-carboxylicacid

607.[2S-[1[R*(R*)]],2α,3αβ,17αβ]-1-[2-[[1-carboxy-3-phenylpropyl]amino]-1-oxopropyl]octahydro-1H-indole-2-carboxylicacid

705. 5-Aminosalicylic acid

707. Methyldopa

708. L-Dopa

710. Valproic acid

714. Tranexamic acid

715. Furosemide

722. Methotrexate

727. Chlorambucil

717. Clofibric acid

720. Amphotericin B

734. 6-Aminocaproic acid

754. Mecillinam

732. Tretinoin

771. 4-Aminomethylbenzoic acid

782. Mycophenolic acid

768. D,L-2,4-Dihydroxyphenylalanin

When R₁ and R₂ are both alkyl, they may be the same or different and arepreferably C₁₋₃ alkyl such as methyl, ethyl, n-propyl or isopropyl. Itis further preferred that n=1. It will be appreciated that in suchpreferred compounds, each and every possible combination of R₁ and R₂(i.e. both being --CH₂ CH₂ OH, or R₁ and R₂ individually being selectedfrom methyl, ethyl, propyl and isopropyl) in the derivative group --CH₂CONR₁ R₂ may, of course, be combined with each and every group R--COOderived from the compounds B listed above, and that the above definitionis equivalent to listing each and every possible combination of thelisted examples of R--COO (from compounds B), R₁ and R₂.

DETAILED DESCRIPTION OF THE INVENTION DOSAGE FORMS AND DOSE

The prodrug compounds of formula I of the present invention can be usedto treat any condition for which the parent carboxylic group containingdrug, medicament or pharmaceutical is useful. For example, if naproxenis the parent drug of choice, the ester prodrug can be used for anycondition or treatment for which naproxen would be administered.

Thus, the prodrug compounds of formula I may be administered orally,topically, parenterally, rectally or by inhalation spray in dosage formsor formulations containing conventional, non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The formulation andpreparation of any of this broad spectrum of dosage forms into which thesubject prodrugs can be disposed is well-known to those skilled in theart of pharmaceutical formulation. Specific information can, however, befound in the text entitled "Remington's Pharmaceutical Sciences",Sixteenth Edition, 1980.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known inthe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavouring agents, colouring agents andpreserving agents in order to provide a pharmaceutically elegant andpalatable preparation.

Formulations for oral use include tablets which contain the activeingredient in admixture with non-toxic pharmaceutically acceptableexcipients. These excipients may be, for example, inert diluents, suchas calcium carbonate, sodium chloride, lactose, calcium phosphate orsodium phosphate; granulating and disintegrating agents, for example,potato starch, or alginic acid; binding agents, for example, starch,gelatin or acacia; and lubricating agents, for example, magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example, peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions usually contain the active materials in admixturewith appropriate excipients. Such excipients are suspending agents, forexample, sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gumtragacanth and gum acacia; dispersing or wetting agents which may be anaturally-occurring phosphatide, for example, lecithin; a condensationproduct of an alkylene oxide with a fatty acid, for example,polyoxyethylene stearate; a condensation product of ethylene oxide witha long chain aliphatic alcohol, for example,heptadecaethyleneoxycetanol; a condensation product of ethylene oxidewith a partial ester derived from fatty acids and a hexitol such aspolyxyethylene sorbitol monooleate; or a condensation product ofethylene oxide with a partial ester derived from fatty acids and hexitolanhydrides, for example, polyoxyethylene sorbitan monooleate. Theaqueous suspensions may also contain one or more preservatives, forexample, methyl, ethyl or n-propyl p-hydroxybenzoate; one or morecolouring agents; one or more flavouring agents; and one or moresweetening agents such as sucrose or saccharin.

Oily suspension may be formulated by suspending the active ingredient ina vegetable oil, for example, arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example, beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of anantioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample, olive oil or arachis oils, or a mineral oil, for example,liquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example, gum acacia or gum tragacanth;naturally-occurring phosphatides, for example, soybean licithin; andesters including partial esters derived from fatty acids and hexitolanhydrides, for example, sorbitan mono-oleate, and condensation productsof the said partial esters with ethylene oxide, for example,polyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, sorbitol or sucrose. Such formulations may also contain ademulcent, a preservative and flavouring and colouring agents, Thepharmaceutical compositions may be in the form of a sterile injectableaqueous or oleagenous suspension. This suspension may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents which have been mentioned above. Thesterile injectable preparation may be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent.Among the acceptable vehicles and solvents that may be employed arewater, 1,3-butanediol, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile fixed oils are conventionally employed asa solvent or suspending medium. For this purpose any bland fixed oil maybe employed including synthetic monoor diglycerides. Fatty acids such asoleic acid also find use in the preparation of injectibles.

The compounds of formula I may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable nonirritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug, for example, cocoa butter, or adeps solidus polyethylene glycols.

For topical use, creams, ointments, jellies, solutions, suspensions orthe like containing the prodrugs are employed according to methodsrecognized in the art.

Naturally, therapeutic dosage range for the compounds of the presentinvention will vary with the size and needs of the patient and theparticular pain or disease symptom being treated. However, generallyspeaking, the following dosage guidelines will suffice. On an oralbasis, the therapeutic dose required for a compound of the presentinvention will generally, on a molecular basis, mimic that for theparent carboxylic acid drug. On a topical basis, application of an 0.01%to 5% concentration of a compound of the present invention (in asuitable topical carrier material) to the affected site should suffice.

From the foregoing description, one of ordinary skill in the art caneasily ascertain the essential characteristics of the present inventionand, without departing from the spirit and scope thereof, can makevarious changes and/or modifications of the invention to adapt it tovarious usages and conditions. As such, these changes and/ormodifications are properly, equitably and intended to be within the fullrange of equivalence of the following claims.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of humans may containfrom 5 mg to 5 gm of the active agent compounded with an appropriate andconvenient amount of carrier material which may vary from about 5 toabout 95% of the total composition. Other dosage forms such asophthalmic dosage forms contain less active ingredient such as forexample from 0.1 mg to 5 mg. Dosage unit forms will generally containbetween from about 0.1 mg to about 500 mg of active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general heath, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and severity of theparticular disease undergoing therapy.

PREPARATION OF THE PRODRUGS OF FORMULA I

The compounds of the present invention can be prepared by a variety ofsynthetic routes. A generally applicable process (method a) comprisesreacting the carboxylic acid agent of the formula A or a salt (e.g. ametal salt) thereof

    R--COOH                                                    (A)

wherein R--COO-- is defined as above in connection with formula I, witha compound having the formula B: ##STR7## wherein n, R₁ and R₂ are asdefined above and X is a suitable leaving group (e.g., halogen such asCl, I or Br, or a methansulfonyloxy or toluenesulfonyloxy group). Thereaction is preferably carried out in a solvent (e.g.N,N-dimethylformamide, water, acetonitrile, a lower alcohol, ethylacetate, toluene or the like). An equivalent of an organic base such astriethylamine, tetramethylguanidine or the like is typically added orcrown ethers are used as phase-transfer catalysts. If X in formula B ischlorine catalytic amounts of an iodide salt may be added to thereaction mixture. The reaction is carried out at a temperature of fromroom temperature to the boiling point of the solvent, and for a periodof time of 0.5 to 48 hours.

Another method (method b) for preparing compounds of the inventioncomprises reacting a compound of the formula B, wherein X is hydroxy,with an acid of the formula A or with the corresponding acid chloride ofthe formula C

    R--COCl                                                    (C)

When an acid starting material is used, i.e. a compound of formula A,the reaction is conducted in the presence of a suitable dehydratingagent, for example N,N-dicyclohexylcarbodiimide. The reaction utilizingan acid starting material is conveniently carried out in an inertsolvent such as dichloromethane, dioxane, pyridine or the like, at atemperature of from 0° to 60° C., for from 1 to 48 h. A catalyst such asp-toluenesulphonic acid or 4-(N,N-dimethylamino)pyridine may be added.When the reaction utilizes an acid chloride starting material, theprocess can be conveniently carried out by reacting the compound offormula B, wherein X is hydroxy, with the desired acid chloride in aninert solvent such as benzene, dichloromethane, dimethylformamide,acetone, dioxane, acetonitrile or the like, at from room temperature toreflux, for from 1 to 24 h, in the presence of an acid scavenger such asan alkali metal carbonate, or an organic base such as triethylamine orpyridine.

The acid chlorides of formula C which can be used in the above methodare prepared from the corresponding acids by known means. e.g. bytreatment of the acid with thionyl chloride or oxalyl chloride. Insteadof acid chlorides acid anhydrides or mixed anhydrides may be used.

The starting materials of formula B, in which X is a halogen, are alsoprepared by known means, e.g. by treatment of the appropriate amine withan appropriately halogen-substituted acid chloride, acid anhydride orester as represented by the following chemical equation for an acidchloride:

    R.sub.1 R.sub.2 NH+X--(CH.sub.2).sub.n COCl→X--(CH.sub.2).sub.n CONR.sub.1 R.sub.2

Several compounds of formula B, in which X is a halogen, and methods fortheir preparation, have been described in the literature, see e.g.Hankins (1965), Weaver and Whaley (1947), Ronwin (1953), Berkelhammer etal. (1961) and Speziale and Hamm (1956).

The starting materials of formula B, in which X is hydroxy, are alsoprepared by known means, e.g. by hydrolysis of2-(acetoxymethyl)acetamides or 2-(benzoyloxymethyl)acetamides. Specificexamples are given below.

Several compounds of formula B, in which X is hydroxy, and methods fortheir preparation, have been described in the literature, see e.g. DEOffen. 2,904,490, DE 2,201,432, and DE 2,219,923.

A third method (method c) for preparing compounds of the presentinvention comprises reacting a compound of the formula D

    HNR.sub.1 R.sub.2                                          (D)

wherein R₁ and R₂ are as defined above in connection with formula I,with an acid of the formula E

    R--COO(CH).sub.n COOH                                      (E)

wherein R--COO-- and n are as defined above in connection with formulaI, or with the corresponding acid chloride (or acid anhydrides) of theformula F

    R--COO(CH.sub.2).sub.n COCl                                (F)

When a compound of formula E is used, the reaction is conducted in thepresence of a suitable dehydrating agent, e.g.N,N-dicyclohexylcarbodiimide. The reaction is conveniently carried outin an inert solvent such as dichloromethane, dioxane, pyridine or thelike, at a temperature of from 0° to 60° C., for from 1 to 48 h. Whenthe reaction utilizes an acid chloride starting material of formula F,the process can be conveniently carried out by reacting the compound offormula F with the desired amine or amine salt in a solvent such asbenzene, dichloromethane, dimethylformamide, acetone, dioxane,acetonitrile, water or the like, at from 0° C. to reflux, for from 1/2to 24 h, in the presence of an acid scavenger such as alkali metalcarbonate, or an organic base such as triethylamine, or an excess of theamine.

The acid chlorides of formula F which can be used in the above methodare prepared from the corresponding acids by known means. e.g. bytreatment of the acid with thionyl chloride or oxalyl chloride.

The acids of formula E which can be used in the above method areprepared from the parent acids (i.e. R--COOH) by known means, e.g. byreacting the acid or a salt of the acid (e.g. a metal ortrimethylammonium salt) with compounds of the formula G

    X--(CH.sub.2).sub.n COOCH.sub.2 C.sub.6 H.sub.5            (G)

wherein X and n are as defined above, or with compounds of the formula H

    X--(CH.sub.2).sub.n CONH.sub.2                             (H)

wherein X and n are as defined above. The intermediates obtainedtherefrom, i.e. R--COO--(CH₂)_(n) COOCH₂ C₆ H₅ and R--COO--(CH₂)_(n)--CONH₂, are subsequently transformed to the compounds of formula E bye.g. hydrogenation or acidic hydrolysis. Several compounds of formula Eand methods for preparing them are known from the literature, see e.g.Boltze et al. (1980) and Concilio & Bongini (1966).

While the basic methods described above can be used to prepare any ofthe compounds of the invention, certain conditions and/or modificationstherein are made in specific instances. Thus, for example, the basicmethods may be modified in the cases where the desired product offormula I contains free aliphatic amino, thiol or hydroxyl groupingswhich, if present in the acid starting material, would undergo undesiredside reaction and/or would interfere with the desired course of theabove-described ester formation. In such cases, the compounds of formulaB or D are reacted with an acid of the formula J

    R.sup.1 --COOH                                             (J)

wherein R¹ --COO-- is the amino-, thiol- or hydroxyl-protected acyloxyresidue of a carboxylic acid agent (R--COOH) containing amino, thiol orhydroxyl groups. The amino, hydroxy or thiol function in the parentacids of the formula RCOOH are converted to their protected counterpartsin formula J by known methods, e.g. those known in the art of peptidesynthesis. For example, amino groups are conveniently protected by thecarbobenzoxycarbonyl or t-butyloxycarbonyl group. The compound offormula J, its corresponding acid chloride or protected counterpart forformula E is subsequently reacted with a compound of formula B or D, asdescribed supra, to afford the compound corresponding to formula I, butcontaining a protected acyloxy residue, i.e. R¹ --COO-- as defined abovein place of R--COO-- in formula I. That protected compound is thendeprotected by known methods, e.g. by hydrogenation or hydrolysis.

The above-described process variations involving the addition andultimate removal of protecting groups is only used when the free amino,hydroxy and/or thiol functions are in need of protection.

When the starting acid of formula I hereinabove is a steroidal acid offormula II, this can be prepared by methods known in the art, forexample by the methods described in U.S. Pat. No. 4,164,504 (Varma). Seealso Chemical Abstracts, 83, 179407 and 84, 122146. Thus, the followingreaction scheme is illustrative of a general method for preparing thedesired acids: ##STR8## wherein R₂₀, R₂₁, R₂₂, R₂₃, Z and the dotted andwavy lines are defined as before. In the cupric acetate reaction, wateris used as a co-solvent with a suitable alcohol, e.g. methanol or otherlower alkanol, and the reaction is allowed to proceed for an extendedperiod of time (more than 24 hours), since decreasing the water presentand lessening reaction time tend to favour formation of the 21-ester ofthe steroid with the alcohol employed. Also, oxygen or air is bubbledthrough the mixture during the course of the reaction to encourageformation of 21-acid rather than 21-aldehyde. In the second step, the20-hydroxy group is oxidized to a 20-keto function by reacting thesteroid of formula XXI with manganese dioxide or lead dioxide in aninert halogenated hydrocarbon solvent such as chloroform ordichloromethane.

DESCRIPTION OF THE DRAWINGS

FIG. 1 shows time courses for naproxen N,N-dimethylglycolamide ester ( )and naproxen (∘) during hydrolysis of the ester in 80% human plasma at37° C. The initial ester concentration was 10⁻⁴ M.

FIG. 2 shows plots of the first-order kinetics of hydrolysis of variousesters (initial concentration being 10⁻⁴ M) in 80% human plasma at 37°C. Key: o, N,N-diethylglycolamide ester of L-phenylalanine; ,N,N-diethylglycolamide ester of naproxen; Δ, N-methyl,N-carbamoylmethylglycolamide ester of ketoprofen.

FIG. 3 shows plot of the rate of hydrolysis of theN,N-dimethylglycolamide ester of salicylic acid in 80% human plasma at37° C.

the present invention is further illustrated by the following exampleswhich, however, are not construed to be limiting. The derivativesdescribed all had spectroscopic properties (IR and ¹ H NMR) andelemental analysis (C, H and N) in agreement with their structures.

EXAMPLE 1 2(BENZOYLOXY)-N,N-DIMETHYLACETAMIDE

Benzoic acid (2.44 g, 0.02 mole) and 2-chloro-N,N-dimethylacetamide(2.43 g, 0.02 mole) were dissolved in 10 ml of N,N-dimethylformamide.Sodium iodide (150, 2 mmol) and triethylamine (2.02 g, 0.02 mole) wereadded and the mixture was stirred at room temperature (20°-25° C.)overnight. After addition of 50 ml of water the reaction mixture wasextracted twice with ethyl acetate. The combined extracts were washedwith a diluted solution of sodium thiosulphate, a 2% aqueous solution ofsodium bicarbonate, water, dried over anhydrous sodium sulphate andevaporated in vacuo. The residue was crystallized from ethanol-water togive 3.5 g (85%) of the title compound. Mp 81°-82° C.

EXAMPLE 2

The compound in Example 1 was also prepared by the following procedure:

2-Chloro-N,N-dimethylacetamide (12.16 g, 0.1 mole) was added to asolution of sodium benzoate (14.4 g, 0.1 mole) and sodium iodide (3.75g, 0.025 mole) in 75 ml of water. The reaction solution was refluxed for2 h. Upon standing overnight at 4° C. the title compound precipitated.It was filtered off, washed with water and recrystallized from aqueousethanol (15.7 g; 76%). Mp 83°-82° C.

EXAMPLE 5 (BENZOYLOXY)ACETYL CHLORIDE

2-Chloroacetamide (18.7 g, 0.2 mole) was added to a solution of sodiumbenzoate (28.8 g, 0.2 mole) and sodium iodide (7.5 g, 0.05 mole) in 150ml of water. The mixture was stirred at 90° C. for 14 h.

Upon cooling to 4° C. 2-(benzoyloxy)acetamide precipitated and wasisolated by filtration. Recrystallization from ethanol-water yielded32.2 g (90%). Mp 120.5°-121° C.

2-(Benzoyloxy)acetamide (19.7 g, 0.11 mole) was added to 200 ml of 7.8Mhydrochloric acid. The mixture was stirred at 75° C. for 10 min. Uponcooling 2-(benzoyloxy)acetic acid precipitated. It was isolated byfiltration, dried and recrystallized from benzene (15.8 g, 80%), M.111°-112° C.

A mixture of 2-(benzoyloxy)acetic acid (12.6 g) and thionyl chloride (15ml) was refluxed for 3 h. Excess of thionyl chloride was removed invacuo and the crude (benzoyloxy)acetyl chloride obtained was purified bydistillation in vacuo. The yield was 88%. Mp 25°-26° C.

EXAMPLE 4 2-(BENZOYLOXY)-(N-METHYL-N-ETHOXYCARBONYLMETHYL)ACETAMIDE

A solution of (benzoyloxy)acetyl chloride (0.8 g , 4 mmole) in 4 ml ofbenzene was added to a cooled (about 5° C.) solution of sarcosine ethylester hydrochloride (0.894 g, 12 mmole) in 6 ml of 2M sodium hydroxide.The mixture was stirred vigorously at room temperature for 2 h. Thelayers were separated and the aqueous phase re-extracted with ethylacetate (20 ml). The combined organic extracts were washed with 2Mhydrochloric acid (10 ml), and dried. Evaporation in vacuo afforded anoily residue which crystallized by trituration with petroleum ether at-20° C.

Recrystallization from ether-petroleum ether yielded the title compound(0.68 g, 61%). Mp 39°-40° C.

EXAMPLE 5

1METHYL-4-(BENZOYLOXYACETYL)PIPERAZINE HYDROCHLORIDE

A solution of 1-methylpiperazine (0.40 g, 4 mmole) in 5 ml benzene wasadded dropwise while stirring to a solution of(benzoyloxy)acetylchloride (0.80 g, 4 mmole) in 10 ml of benzene. Afterthe addition was completed (about 10 min) the reaction mixture wasstirred at room temperature for 1 h. Ether (10 ml) was added and themixture was filtered. The white crystalline compound on the filter waswashed with ether and finally recrystallized from ethanol, yielding 0.70g (59%) of the title compound. Mp 227°-228° C.

EXAMPLE 6 2-BENZOYLOXY)-(N-METHYL-N-βHYDROXYETHYL)ACETAMIDE

A solution of (benzoyloxy)acetyl chloride (1.5 g, 8 mmole) in 8 ml ofbenzene was mixed with N-methylethanolamine (1.8 g, 24 mmole). Thesolution was stirred at room temperature for 3 h and then concentratedin vacuo. The residue was dissolved in ethyl acetate (50 ml) and water(10 ml). The layers were separated and the organic phase washed with 2Mhydrochloric acid (5 ml), water (5 ml), dried and evaporated in vacuo.The residue crystallized by trituration with ether and standingovernight at -20° C. The compound was filtered off and recrystallizedfrom ethyl acetate-petroleum ether, giving 1.1 g (50%) of the titlecompound. Mp 78°-80° C.

EXAMPLE 7 2-(BENZOYLOXY)-N,N-(DICARBAMOYLMETHYL)ACETAMIDE

A solution of (benzoyloxy)acetyl chloride 0.8 g. 4 mmole) in benzene (4ml) was added while stirring at room temperature to a mixture ofiminodiacetamide hydrochloride (1.06 g, 6 mmole) and sodium bicarbonate(2.52 g, 30 mmole) in water (5 ml). The mixture was stirred for 3 h. Theprecipitate formed was filtered off, washed with a small amount of waterand recrystallized from water to give 0.70 g (60%) of the titlecompound. Mp 195°-196° C.

EXAMPLE 8 N-(BENZOYLOXYMETHYLCARBONYL)PYRROLIDONE

A mixture of (benzoyloxy)acetyl chloride (1.98 g, 0.01 mole),pyrrolidone (0.85 g, 0.01 mole) and pyridine (0.8 g, 0.01 mole) inacetone (10 ml) was refluxed for 3 h. The cooled mixture was filteredand evaporated in vacuo. The residue was dissolved in ethyl acetate (50ml) and the solution washed with a 2% aqueous solution of sodiumbicarbonate, 2M hydrochloric acid and water. After drying over anhydroussulphate, the organic phase was evaporated under reduced pressure togive a residue which crystallized by addition of ether.Recrystallization from ether-petroleum ether yielded 1.6 g (65%) of thetitle compound. Mp 83°-84° C.

EXAMPLES 9-33

By following the procedures of the foregoing examples several moreesters of benzoic acid according to the invention were prepared. Thestructure of these esters and their melting points are shown in Table 1.

EXAMPLE 342-[1-(P-CHLOROBENZOYL)-5-METHOXY-2-METHYLINDONE-3-ACETYLOXY]-N,N-DIETHYLACETAMIDE

Indomethacin (1.43 g, 4 mmole) and 2-chloro-N,N-diethylacetamide (0.61g, 4.1 mmole) were dissolved in 5 ml of N,N-dimethylformamide andtriethylamine (0.56 ml, 4 mmole) and sodium iodide (60 mg) added. Themixture was stirred at room temperature for 20 h and poured into 50 mlof water. The mixture was extracted with ethyl acetate (2×50 ml). Theextract was washed with 2% aqueous solution bicarbonate and water. Afterdrying over anhydrous sodium sulphate the organic phase was evaporatedin vacuo. The residue was recrystallized from ethyl acetate-petroleumether, yielding 1.6 g (90%) of the title compound. Mp 148°-149° C.

                  TABLE 1                                                         ______________________________________                                         ##STR9##                                                                      ##STR10##                                                                    ______________________________________                                        Example                                                                       number  n     R.sub.1     R.sub.2    Mp (°C.)                          ______________________________________                                         9      1     CH.sub.3    C.sub.2 H.sub.5                                                                          ˜20                                10      1     C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                          62.5-63.5                                11      1     C.sub.3 H.sub.7                                                                           C.sub.3 H.sub.7                                                                          ˜20                                12      1     iC.sub.3 H.sub.7                                                                          iC.sub.3 H.sub.7                                                                         104.5-105.5                              13      1     CH.sub.2 CHCH.sub.2                                                                       CH.sub.2 CHCH.sub.2                                                                      42-43                                    14      1     nC.sub.4 H.sub.9                                                                          nC.sub.4 H.sub.9                                                                         ˜25                                15      1     iC.sub.4 H.sub.9                                                                          iC.sub.4 H.sub.9                                                                         44-45                                    16      1     CH.sub.3    CH.sub.2 CH.sub.2 OH                                                                     78-80                                    17      1     CH.sub.2 CH.sub.2 OH                                                                      CH.sub.2 CH.sub.2 OH                                                                     80-82                                    18      1     CH.sub.3    CH.sub.2 CONH.sub.2                                                                      101-102                                  19      1     CH.sub.3    C.sub.6 H.sub.11                                                                         100-101                                  20      1     C.sub.6 H.sub.11                                                                          C.sub.6 H.sub.11                                                                         162-163                                  21      2     CH.sub.3    CH.sub.3   <20                                      22      3     CH.sub.3    CH.sub.3   40-41                                    23      1     C.sub.2 H.sub.5                                                                           CH.sub.2 CH.sub.2 OH                                                                     79-80                                     23a    1     CH.sub.3    CH.sub.2 CH.sub.2 N                                                                      158-159                                                            (CH.sub.3).sub.2, HCl                                23b    1     CH.sub.2 CH.sub.2 OCH.sub.3                                                               CH.sub.2 CH.sub.2 OCH.sub.3                                                              57-58                                    ______________________________________                                        Example                                                                       number  n     R.sub.1              Mp (°C.)                            ______________________________________                                        24      1                                                                                    ##STR11##           74-75                                      25      1                                                                                    ##STR12##           57.5-58                                    26      1                                                                                    ##STR13##           87-88                                      27      1                                                                                    ##STR14##           107-108                                    28      1                                                                                    ##STR15##           103-104                                    29      1                                                                                    ##STR16##           118-118.5                                  30      1                                                                                    ##STR17##           194-195                                    31      1                                                                                    ##STR18##           72-73                                      32      1                                                                                    ##STR19##           121-122                                    33      1                                                                                    ##STR20##           228-229                                     33a    1                                                                                    ##STR21##           54-55                                      ______________________________________                                    

EXAMPLE 352-[(+)-6-METHOXY-α-METHYL-2-NAPHTHALENEACETYLOXY]-N,N-DIETHYLACETAMID

Naproxen (1.07 g, 5 mmole) and 2-chloro-N,N-diethyl-acetamide (0.90 g, 6mmole) were dissolved in 7 ml of N,N-dimethylformamide and triethylamine(1.4 ml, 10 mmole) and sodium iodide (76 mg) were added. The mixture wasrefluxed for 2 h, cooled and poured into 35 ml of water. The precipitateformed after standing overnight at 4° C. was collected by filtration,washed with water and recrystalized from 95% ethanol, yielding 1.5 g(92%) of the title compound. Mp 89°-89.5° C.

EXAMPLE 36 2-[2-(ACETYLOXY)BENZOYLOXY]-N,N-DIETHYLACETAMIDE

To a mixture of acetylsalicylic acid (5.4 g. 0.03 mole) and2-chloro-N,N-diethylacetamide (4.5 g, 0.03 mole) in 40 ml of ethylacetate was added triethylamine (4.2 ml, 0.03 mole) and sodium iodide(0.45 g, 0.003 mole). The mixture was refluxed for 4 h. After coolingthe mixture was filtered and the filtrate washed with 2M hydrochloricacid, 5% sodium bicarbonate and water. After drying over anhydroussodium sulphate the solution was evaporated in vacuo leaving an oilwhich crystallized by trituration with ethanol. Recrystallization from80% ethanol afforded 6.2 g (70%) of the title compound. Mp 75°-76° C.

EXAMPLE 372-[2-HYDROXYBENZOYLOXY]-(N-METHYL-N-CARBAMOYLMETHYL)-ACETAMIDE

The ester was prepared from salicylic acid andN-chloroacetylsarcosinamide (prepared as described in Example 87) by theprocedure described in Example 1. The crude product was recrystallizedfrom ethyl acetate-ether. Mp 142°-143° C.

EXAMPLE 38 2-(L-PHENYLALANYLOXY)-N,N-DIETHYLACETAMIDE HYDROBROMIDE

A solution of N-benzyloxycarbonyl-L-phenylalanine (3.0 g, 0.01 mole).2-chloro-N,N-diethylacetamide (1.57 g, 0.011 mole) and triethylamine(1.4 ml, 0.01 mole) in acetonitrile (15 ml) was refluxed for 6 h.evaporated to dryness in vacuo, and diluted with saturated aqueoussodium bicarbonate solution. N-Benzyloxycarbonyl-L-phenylalanineN-N-diethylglycolamide ester was collected by filtration, washed withwater and recrystallized from ethanol-water. Mp 85.5°-86.5° C.

This compound (2.0 g) was treated with 10 ml of 33% hydrogen bromide inacetic acid for 1 h at room temperature. Addition of ether precipitatedthe title compound, which was washed with ether and recrystallized frommethanol-ether. Mp 95°-97° C.

EXAMPLE 392-[1-(P-CHLOROBENZOYL)-5-METHOXY-2-METHYLINDOLE-3-ACETYLOXY]-N,N-DIMETHYLACETAMIDE

a. To a stirred suspension of indomethacin (3.58 g, 0.01 mole) inbenzene (10 ml) at 60° C. was added dropwise thionyl chloride (1.12 ml,0.015 mole). The mixture was stirred for 1 h at 65°-70° C. andconcentrated to about 5 ml in vacuo. Hot petroleum ether (25 ml) wasadded and the mixture filtered to give 3.2 g (85%) of1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetyl chloride (acidchloride of indomethacin). Mp 126°-127° C.

b. 2-Hydroxy-N,N-dimethylacetamide was prepared by alkaline hydrolysisof 2-(benzoyloxy)-N,N-dimethylacetamide obtained as described inExample 1. 2-(Benzoyloxy)-N,N-dimethylacetamide (20.7 g, 0.1 mole) wasdissolved in 50 ml of ethanol by heating to 40°-50° C. Potassiumhydroxide (2M, 70 ml) was added and the mixture allowed to stand at roomtemperature for 1 h. The pH of the solution was adjusted to 8.9 byaddition of 4M hydrochloric acid and the ethanol removed in vacuo. ThepH of the mixture was adjusted to 3.5-4 with hydrochloric acid.Precipitated benzoic acid was filtered off and the filtrate was madealkaline (pH 8-9) with potassium hydroxide. The solution was evaporatedin vacuo. The semi-solid residue obtained was slurried in ethyl acetate(100 ml) and the mixture heated to about 60° C. It was filtered, driedover sodium sulphate and evaporated in vacuo to give crude2-hydroxy-N,N-dimethylacetamide. This extraction process was repeatedtwice. Recrystallization from ether-petroleum ether afforded 7.1 g (69%)of the compound. Mp 49°-50° C.

c. Indomethacin acid chloride (1.14 g, 3 mmole) was added in portions toa solution of 2-hydroxy-N,N-dimethylacetamide (340 mg, 3.3 mmole) inacetonitrile (3 ml) and pyridine (320 g, 4 mmole). cooled to 0°-4° C.The mixture was stirred at room temperature for 4 h and evaporated invacuo. The residue was taken up in a mixture of water and ethyl acetate.The organic base was separated and washed with 1M hydrochloric acid, 5%sodium bicarbonate and water. Evaporation of the dried solution affordeda solid residue which upon recrystallization from ethyl acetate affordedthe title compound. Mp 149°-150° C.

EXAMPLE 40 2-(4-AMINOBENZOYLOXY)-N,N-DIETHYLACETAMIDE

A mixture of 4-aminobenzoic acid (1.37 g. 0.01 mole),2-chloro-N,N-diethylacetamide 2.0 ml, 0.015 mole) and1.8-diazabicyclo[5.4.0]-undec-7-ene (1.52 g, 0.01 mole) in benzene (20ml) was stirred at 80° C. for 4 h and then evaporated in vacuo. Theresidue was taken up in ethyl acetate. After washing with 5% sodiumbicarbonate and water the ethyl acetate extract was dried and evaporatedin vacuo leaving crude title compound. Recrystallization fromethanol-water gave 1.5 g (60%). Mp 135°-136° C.

EXAMPLE 412-[α-METHYL-4-(2-METHYLPROPYL)BENZENEACETYLOXY]-(N-METHYL-N-CARBAMOYLMETHYL)ACETAMIDE

A mixture of ibuprofen (1.03 g, 5 mmole), 2-chloroacetylsarcosinamide(0.82 g, 5 mmole), triethylamine (0.8 ml, 5.7 mmole) and sodium iodide(100 mg) in N,N-dimethylformamide (10 ml) was stirred at roomtemperature for 20 h. Water (50 ml) was added and the mixture allowed tostand at 4° C. for 5 h. The title compound precipitated was isolated byfiltration, washed with water and recrystallized from ethanol-water togive 1.35 g (81%). Mp 100°-100.5° C.

EXAMPLE 422-[2-[(2,3-DIMETHYLPHENYL)AMINO]-BENZOYLOXY]-N,N-DIMETHYLACETAMIDE

A mixture of mefenamic acid (2.41 g, 0.01 mole),2-chloro-N,N-dimethylacetamide (1.6 g, 0.013 mole), triethylamine (1.6ml, 0.011 mole) and sodium iodide (0.15 g, 0.001 mole) inN,N-dimethylformamide (10 ml) was stirred at 90° C. for 2 h. Water (50ml) was added and the mixture allowed to stand at 4° C. for 5 h. Thetitle compound was isolated by filtration, washed with water andrecrystallized from ethanol-water (3.0 g, 92%). Mp 85°-86° C.

EXAMPLE 432-[1-METHYL-5-(α-METHYLBENZOYL)-2H-PYRROLE-2-ACETYLOXY]-N,N-DIMETHYLACETAMIDE

A mixture of tolmetin (1.29 g, 5 mmole), 2-chloro-N,N-dimethylacetamide(0.74 g, 6 mmole), triethylamine (0.84 ml, 6 mmole) and sodium iodide(50 mg) in N,N-dimethylformamide (10 ml) was stirred at 90° C. for 3 h.Water (50 ml) was added and the mixture extracted with ethyl acetate (75ml). After washing with an aqueous bicarbonate solution and water theextract was dried and evaporated in vacuo. The residue obtainedcrystallized upon standing at -20° C. and was recrystallized fromethanol-ether to give 1.3 g (76%) of the title compound. Mp 108°-109° C.

EXAMPLE 442-[(+)-6-METHOXY-α-METHYL-2-NAPHTHALENEACETYLOXY]-N,N-(DI-β-HYDROXYETHYL)ACETAMIDE

The compound was prepared from naproxen and2-chloro-N,N-(di-β-hydroxyethyl)acetamide by the procedure described inExample 1. The yield was 60%. Recrystallization from ethyl acetate gavean analytically pure product. Mp 113°-114° C.

EXAMPLE 45 2-[(+)-6-METHOXY-60-METHYL-2-NAPHTHALENEACETYLOXY]-(N-METHYL-N-βHYDROXYETHYL)ACETAMIDE

The compound was prepared from naproxen and 2-chloro(N-methyl-N-βhydroxyethyl)acetamide by the procedure described inExample 1. The yield was 65%. Recrystallization from ethyl acetate gavean analytically pure product. Mp 109°-111° C.

EXAMPLE 46 2-(6-PHENYLACETAMIDOPENICILLANOYLOXY)-N,N-DIETHYL-ACETAMIDE

A mixture of benzylpenicillin sodium (1.78 g, 5 mmole),2-chloro-N,N-diethylacetamide (1.05 g, 7 mmole) and sodium iodide (75mg) in N-N-dimethylformamide (10 ml) was stirred at room temperature for18 h. Water (60 ml) was added and mixture extracted with ethyl acetate(2×50 ml). The extract was washed with 5% aqueous sodium bicarbonate andwater. Evaporation of the dried organic phase in vacuo yielded a residuewhich crystallized from ethanol-water. Mp 60°-61° C.

EXAMPLE 472-(BENZOYLOXY)-(N-METHYL-N-(N,N-DIMETHYLGLYCYLOXYETHYL)ACETAMIDE(MONOFUMARATE)

A mixture of 2-(benzoyloxy)-(N-methyl-N-β-hydroxyethyl)-acetamide (0.95g, 4 mmole), N,N-dimethylglycine (0.41 g, 4 mmole),N,N'-dicyclohexylcarbodiimide (0.82 g, 4 mmole) and 4-toluenesulfonicacid (50 mg) in pyridine (10 ml) was stirred at room temperature for 24h Methylene chloride (20 ml) was added. The mixture was filtered and thefiltrate was evaporated in vacuo. The residue was extracted with 20 mlof boiling ethyl acetate and the extract was evaporated. The oilyresidue obtained was dissolved in ether (20 ml) and a solution offumaric acid in 2-propanol was added. After standing overnight at 4° C.the title compound was isolated by filtration in a yield of 59%.Recrystallization from methanol-ether gave an analytically pure product.Mp 127°-127.5° C.

EXAMPLE 48 2-(L-4-HYDROXYPHENYLALANYLOXY)-N,N-DIETHYLACETAMIDEHYDROCHLORIDE

A mixture of N-tert-butoxycarbonyl L-tyrosine (Boc-L-tyrosine) (1.41 g,5 mmol), 2-chloro-N,N-diethylacetamide (0.68 ml, 5 mmol), tri-ethylamine(0.7 ml, 5 mmol) and sodium iodide (75 mg, 0.5 mmol) inN,N-dimethylformamide (5 ml) was stirred overnight at room temperature.Water (50 ml) was added and the mixture extracted with ethyl acetate(2×50 ml). After washing with an aqueous sodium bicarbonate solution andwater the combined extracts were dried and evaporated in vacuo. Thesolid residue was recrystallized from ethyl acetate to give 1.3 g ofBoc-L-tyrosine ester of 2-hydroxy-N,N-diethylacetamide, Mp 130°-131° C.

This ester was deprotected by stirring 0.5 g in 3 ml of 2.5M methanolicHCl. After 1 h a clear solution was obtained. The solution wasevaporated in vacuo and the oily residue crystallized fromethanol-ether. Mp 164°-166° C.

EXAMPLE 49 2-(4-HYDROXYBENZOYLOXY)-N,N-DIETHYLACETAMIDE

A mixture of 4-hydroxybenzoic acid (1.38 g, 0.01 mol),2-chloro-N,N-diethylacetamide (1.4 g, 0.01 mol) triethylamine (1.44 ml.0.01 mol) and sodium iodide (150 mg, 0.001 mol) in N,N-dimethylformamide(6 ml) was stirred at room temperature for 18 h. Water (100 ml) wasadded and the mixture allowed to stand at 4° C. for 5 h. The titlecompound was isolated by filtration, washed with water andrecrystallized from ethanol-water to give 1.8 g. Mp 148°-149° C.

EXAMPLE 502-TRANS-4-(AMINOMETHYL)CYCLOHEXANOYLOXY)-N,N-DIMETHYLACETAMIDEHYDROCHLORIDE

Tranexamic acid (3.0 g, 0.019 mol) was dissolved in 12 ml of thionylchloride. The solution was kept at room temperature for 30 min. Uponaddition of ether the acid chloride of tranexamic acid as hydrochloridesalt precipitated. It was filtered off and dried over P₂ O₅ in vacuo, mp138°-139° C.

The acid chloride (2.10 g, 0.01 mol) was added portionwise and whilestirring to a solution of 2-hydroxy-N,N-dimethylacetamide (1.24 g, 0.012mol) in 10 ml of dioxane. The solution was stirred at 60° C. for 1 h andthen cooled to 0°-4° C. The precipitate formed was filtered off andrecrystallized from ethanol to give 1.5 g of the title compound, mp183°-184° C.

EXAMPLE 512-[α-METHYL-4-(2-METHYLPROPYL)BENZENEACETYLOXY]-(N-METHYL-N-(N'-MORPHOLINOMETHYLCARBAMOYL)METHYL)ACETAMIDEHYDROCHLORIDE

2-[α-Methyl-4-(2-methylpropyl)benzeneacetyloxy]-(N-methyl-N-carbamoylmethyl)acetamide(0.67 g, 2 mmol), prepared as described in Example 49, was dissolved in2.5 ml of methanol. Morpholine (0.18 g. 2 mmol) and 0.17 ml of 37%aqueous formaldehyde solution were added The solution was heated on asteam bath for 15 min. and evaporated in vacuo. The oily residue wasdissolved in ether (10 ml) and a 2.5M methanolic solution of HCl (1 ml)was added followed by petroleum ether. The mixture was kept overnight at-20° C. to allow precipitation of the title compound which was isolatedby filtration, mp 154°-155° C.

EXAMPLES 52-86

By following the procedures of the foregoing examples several more novelesters of the present invention were prepared. The structure of theseesters along with their melting points are shown in Table 2.

                                      TABLE 2                                     __________________________________________________________________________    Compounds of Formula I wherein n = 1                                          Example                                                                            R--COO-- is the                                                          number                                                                             acyloxy residue of:                                                                      R.sub.1                                                                              R.sub.2  Mp (°C.)                               __________________________________________________________________________    52   Naproxen   CH.sub.3                                                                             CH.sub.3 150-151                                       53   Naproxen   CH.sub.3                                                                             CH.sub.2 CONH.sub.2                                                                    179-180                                       54   Ibuprofen  CH.sub.3                                                                             CH.sub.3 oil                                           55   Ketoprofen CH.sub.3                                                                             CH.sub.3 oil                                           56   Ketoprofen C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                        oil                                           57   4-Biphenylacetic                                                                         CH.sub.3                                                                             CH.sub.2 CONH.sub.2                                                                    174-175                                            acid                                                                     58   Flurbiprofen                                                                             CH.sub.3                                                                             CH.sub.3 74-75                                         59   Flurbiprofen                                                                             C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                        60-61                                         60   Fenbufen   CH.sub.3                                                                             CH.sub.3 120-121                                       61   Fenbufen   C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                        94-95                                         62   Indomethacin                                                                             C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                        104-105                                       63   Indomethacin                                                                             CH.sub.3                                                                             CH.sub.2 CH.sub.2 OH                                                                   138-139                                       64   Indomethacin                                                                             CH.sub.2 CH.sub.2 OH                                                                 CH.sub.2 CH.sub.2 OH                                                                   144-146                                       65   Tolfenamic acid                                                                          CH.sub.3                                                                             CH.sub.3 106-107                                       66   Tolfenamic acid                                                                          C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                        114-115                                       67   Tolfenamic acid                                                                          C.sub.2 H.sub.5                                                                      CH.sub.2 CH.sub.2 OH                                                                   85-86                                         68   Tolfenamic acid                                                                          CH.sub.2 CH.sub.2 OH                                                                 CH.sub.2 CH.sub.2 OH                                                                   176-180                                       69   Diflunisal CH.sub.3                                                                             CH.sub.3 96.5-97                                       70   Diflunisal C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                        75-76                                         71   Mephenamic acid                                                                          CH.sub.3                                                                             CH.sub.2 CH.sub.2 OH                                                                   176-180                                       72   L-methyldopa                                                                             C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                        122-124                                       73   Sulindac   C.sub.2 H.sub.3                                                                      C.sub.2 H.sub.5                                                                        100-101                                       74   Benzylpenicillin                                                                         CH.sub.3                                                                             CH.sub.3 71-72                                         75   Furosemide CH.sub.3                                                                             CH.sub.3 193-194                                       76   Mecillinam C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                        120-122                                       77   Valproic acid                                                                            CH.sub.3                                                                             CH.sub.3 oil                                           78   Valproic acid                                                                            CH.sub.3                                                                             CH.sub.2 CONH.sub.2                                                                    57-58                                         79   Salicylic acid                                                                           CH.sub.3                                                                             CH.sub.3 67.5-68                                       80   Salicylic acid                                                                           C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                          73-74.5                                     81   Acetylsalicylic acid                                                                     C.sub.3 H.sub.7                                                                      C.sub.3 H.sub.7                                                                        49.5-50.5                                     82   Acetylsalicylic acid                                                                     iC.sub.3 H.sub.7                                                                     iC.sub.3 H.sub.7                                                                       108-109                                       83   Acetylsalicylic acid                                                                     CH.sub.3                                                                             CH.sub.2 COOC.sub.2 H.sub.5                                                            47-48                                         84   Acetylsalicylic acid                                                                     CH.sub.3                                                                             CH.sub.2 CONH.sub.2                                                                    123-124                                       85   Acetylsalicylic acid                                                                     C.sub.6 H.sub.11                                                                     C.sub.6 H.sub.11                                                                       133-134                                       86   Acetylsalicylic acid                                                                     morpholine      97-99                                         __________________________________________________________________________

EXAMPLE 87 PREPARATION OF α-CHLOROACETYLSARCOSINAMIDE

Sarcosinamide hydrochloride was prepared by reacting methylamine with2-chloroacetamide as described by Marvel et al. (1946). The compound wasrecrystallized from ethanol. Mp 160°-161° C.

A solution of chloroacetyl chloride (0.1 mole, 11.3 g) in benzene (40ml) was added over 30 min to a mixture of sarcosinamide hydrochloride(0.1 mole, 12.45 g) and sodium bicarbonate (0.25 mole, 20.0 g) in 40 mlof water. The mixture was vigorously stirred for 3 h at roomtemperature. The aqueous phase was acidified with 5M hydrochloric acidto pH 5 and extracted with ethyl acetate (3×400 ml). The combinedextracts were dried over anhydrous sodium sulphate and evaporated invacuo. The solid residue obtained was recrystallized from ethanol-etherto give 8.5 g (52%) of the title compound. Mp 85°-86° C.

EXAMPLE 88 2-(ACETYLOXY)-N,N-DIMETHYLACETAMIDE

A suspension of anhydrous sodium acetate (16.4 g, 0.2 mole) and2-chloro-N,N-dimethylacetamide (24.3 g, 0.2 mole) in toluene (70 ml) wasrefluxed for 4 h. After cooling to room temperature the mixture wasfiltered and the filtrate washed with water (2×10 ml), dried andevaporated in vacuo. The solid residue obtained was recrystallized fromether yielding 22.0 g (76%). Mp 52°-53° C.

IN-VITRO CLEAVAGE OF ESTER PRODRUGS Reaction conditions

Solutions of various derivatives of this invention in aqueous buffersolutions or 50-80% human plasma solutions (pH 7.4) were kept at 37° C.The initial concentration of the derivatives was in the range 3×10⁻⁴-10⁻⁵ M. At various times an aliquot of the solutions was withdrawn andanalyzed by HPLC for remaining derivative as well as for parent acid.For the plasma solutions the aliquot withdrawn was deproteinized withmethanol, ethanol or acetonitrile and after centrifugation, the clearsupernatant was injected on HPLC.

Analytical method

An HPLC method was used for the determination of the ester derivativesand their parent acids. In this method a reversed-phase LiChrosorb RP-8column (250×4 mm) was eluted at ambient temperature with mixtures ofmethanol and 0.01M acetate buffer pH 5.0, methanol and 0.01M phosphatebuffer pH 4.5 or methanol and 0.02M phosphate buffer pH 3.5. thecomposition of the eluant was adjusted for each compound in order toprovide an appropriate retention time and separation of ester and thecorresponding acid. The flow-rate was 0.6-1.6 ml/min and the columneffluent was monitored spectrophotometrically at an appropriatewavelength. Quantitation of the compounds was done by measurement of thepeak heights in relation to those of standards chromatographed under thesame conditions.

The various prodrug esters were found to be cleaved quantitatively tothe parent acids in human plasma solutions. An example is shown inFIG. 1. The esters of the present invention hydrolyzed surprisinglyrapidly in human plasma although the rate of hydrolysis depends greatlyon the substituents R₁ and R₂ in Formula I. The half-lives of hydrolysisof various derivatives in 50% human plasma solutions (pH 7.4; 37° C.)are given in Table 3. As can be seen from the data the N,N-disubstituted2-(acyloxy)acetamide esters are particularly rapidly hydrolyzed. Thus,the half-life for the hydrolysis of 2-(benzoyloxy)-N,N-diethylacetamideis less than 3 sec. In pure buffer solution of the same pH (7.4) and at37° C. the half-life of hydrolysis of this compound and the relatedesters listed in Table 3 was found to be greater than 1,000 h, thusdemonstrating the facile enzymatic hydrolysis at conditions similar tothose prevailing in vivo.

At initial concentrations of about 10⁻⁴ M the progress of hydrolysis ofsome esters followed strict first-order kinetics (examples are shown inFIG. 2), whereas in other cases mixed kinetics was observed. An exampleof the latter is shown in FIG. 3. As seen from FIG. 3 the rate ofhydrolysis initially followed zero-order kinetics and as the substratedepleted, it changed to follow first-order kinetics. This behaviour istypical for enzyme-catalyzed reactions in which the initial substrateconcentration is higher than the Michaelis constant K_(m). At lowsubstrate concentrations, i.e. concentrations similar to thoseprevailing in vivo for prodrug hydrolysis, the enzymatic reaction isfirst-order with the half-lives referred to in Table 3.

Table 4 shows hydrolysis data for esters of various carboxylic acidsaccording to the present invention. The structure of the acyl moiety hasan influence on the enzymatic reactivity but in all cases a quite rapidrate of hydrolysis in plasma was observed. By comparing the rates ofhydrolysis of the esters of the present invention with those of thecorresponding simple methyl or ethyl esters (Table 5) the much morefacile enzymatic hydrolysis of the esters disclosed herein is readilyapparent.

The esters of the present invention were found to be highly stable inacidic media. For example, no hydrolysis, i.e. (<1%), of2-(benzoyloxy)-N,N-diethylacetamide was found to take place in 0.01M HClsolutions kept at 37° C. for 3 h.

These results show that the esters of the present invention combine ahigh susceptibility to undergo enzymatic hydrolysis in plasma with ahigh stability in aqueous solution, e.g. in acidic medium such asgastric juices. In consequence, for example, the esters will remainintact in the gastro-intestinal tract upon oral administration, therelease of the free carboxylic acid agent occurring during theabsorption process or in the blood following absorption.

WATER-SOLUBILITY AND LIPOPHILICITY OF THE ESTER PRODRUGS

The partition coefficients (P) for some esters of the present inventionwere measured at 22° C. using the widely-used octanol-water system.Similarly, the solubility of the derivatives in water or aqueous buffersolutions was determined. The values found for log P and thewater-solubilities are included in Table 3.

The results obtained show that by varying the substituents R₁ and R₂ andn in Formula I it is readily feasible to obtain ester prodrugderivatives with varying and any desirable lipophilicity orwater-solubility with retainment of a great lability to enzymatichydrolysis. Thus, as seen from Table 3, the derivative2-(benzoyloxy)-N-N-(di-β-hydroxyethyl)acetamide is soluble in water toan extent of more than 70% w/v although it is a neutral compound with apositive log P value. As a further example, the corresponding esterderivative of naproxen (Example 44) was found to be more than 20-foldmore soluble in 0.01M HCI than parent naproxen.

BIOAVAILABILITY STUDY

The naproxen prodrug derivative described in Example 44 was administeredorally to rabbits. Similarly, naproxen itself was given orally torabbits in an equivalent dose (4.8 mg/kg naproxen). After drugadminstration, blood samples were taken at various times and the plasmafraction assayed for naproxen and prodrug using an HPLC method at thefollowing conditions: Column: LiChrosorb RP-8; eluent: methanol-0.02MKH₂ PO₄ (pH 3.5) 65:35; detection: UV at 230 nm.

As seen from Table 6 the naproxen prodrug derivative is efficientlyabsorbed following oral administration. No measurable concentrations(<0.1 μg/ml) of intact naproxen prodrug were observed, thusdemonstrating that the prodrug is rapidly converted back to naproxen invivo in accordance with the "prodrug" definition provided at the outsetof this application.

                  TABLE 3                                                         ______________________________________                                        Rates of enzymatic hydrolysis, water-solubility and partition                 coefficients for various compounds of the formula                              ##STR22##                                                                    ______________________________________                                                                     S.sup.a                                                                              log  t.sub.1/2.sup.c                      R.sub.1   R.sub.2      n     (mg/ml)                                                                              P.sup.b                                                                            (min)                                ______________________________________                                        CH.sub.3  CH.sub.3     1     8.8    1.07 0.15                                 CH.sub.3  C.sub.2 H.sub.5                                                                            1     --     1.27 0.10                                 C.sub.2 H.sub.5                                                                         C.sub.2 H.sub.5                                                                            1     2.0    2.06 0.04                                 nC.sub.3 H.sub.7                                                                        nC.sub.3 H.sub.7                                                                           1     1.1    2.65 0.14                                 iC.sub.3 H.sub.7                                                                        iC.sub.3 H.sub.7                                                                           1     0.12   2.56 0.08                                 CH.sub.2 CHCH.sub.2                                                                     CH.sub.2 CHCH.sub.2                                                                        1     0.71   2.34 0.08                                 nC.sub.4 H.sub.9                                                                        nC.sub.4 H.sub.9                                                                           1     0.080  3.91 3.1                                  iC.sub.4 H.sub.9                                                                        iC.sub.4 H.sub.9                                                                           1     0.081  3.80 <1.5                                 CH.sub.3  C.sub.6 H.sub.11                                                                           1     0.14   2.99 0.54                                 C.sub.6 H.sub.11                                                                        C.sub.6 H.sub.11                                                                           1     0.0034 --   407                                  CH.sub.3  CH.sub.2 CH.sub.2 OH                                                                       1     19.3   0.58 0.20                                 C.sub.2 H.sub. 5                                                                        CH.sub.2 CH.sub.2 OH                                                                       1     10.8   0.93 0.16                                 CH.sub.2 CH.sub.2 OH                                                                    CH.sub.2 CH.sub.2 OH                                                                       1     720    0.17 0.42                                 CH.sub.3  CH.sub.2 CH.sub.2 OOC                                                                      1     >200   --   0.08                                           CH.sub.2 N(CH.sub.3).sub.2.sup.d                                    CH.sub.3  CH.sub.2 CONH.sub.2                                                                        1     30.2   0.08 0.13                                 CH.sub.3  CH.sub.2 COOC.sub.2 H.sub.5                                                                1     6.0    1.56 0.22                                 CH.sub.3  CH.sub.3     2     17.6   1.28 5.6                                  CH.sub.3  CH.sub.3     3     13.9   1.86 14.1                                 CH.sub.3  CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2.sup.d                                                  1     >100   --   0.12                                 CH.sub.2 CH.sub.2 OCH.sub.3                                                             CH.sub.2 CH.sub.2 OCH.sub.3                                                                1     --     --   0.25                                 ______________________________________                                         ##STR23##     n      (mg/ml)S.sup.a                                                                          log P.sup.b                                                                          (min)t.sub.1/2.sup.c                   ______________________________________                                         ##STR24##    1      5.4       1.20   0.83                                     ##STR25##    1      6.3       1.44   5.7                                      ##STR26##    1      0.78      1.95   2.5                                      ##STR27##    1      0.75      2.30   1.0                                      ##STR28##    1      4.2       0.90   4.9                                      ##STR29##    1      --        --     5.8                                      ##STR30##    1      0.15      2.90   0.40                                     ##STR31##    1      1.5       0.20   2.3                                      ##STR32##    1      2.4       1.42   1.9                                      ##STR33##    1      0.49      1.83   18                                       ##STR34##    1      >100      --     12.7                                    ______________________________________                                         .sup.a Solubility in water at 22° C.                                   .sup.b P is the partition coefficient between octanol and water at            22° C.                                                                 .sup.c Half-life of hydrolysis in 50% human plasma (pH 7.4) at 37°     C.                                                                            .sup.d Hydrochloride salt                                                

                                      TABLE 4                                     __________________________________________________________________________    Half-lives (t.sub.1/2) of hydrolysis of various compounds of the formula       ##STR35##                                                                    RCOO is the                                                                   acyloxy residue of                                                                        R.sub.1                                                                              R.sub.2       t.sub.1/2  (min)                             __________________________________________________________________________    Naproxen    CH.sub.3                                                                             CH.sub.3      1.5                                                      C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                             0.6                                                      CH.sub.2 CH.sub.2 OH                                                                 CH.sub.2 CH.sub.2 OH                                                                        1.3                                                      CH.sub.3                                                                             CH.sub.2 CONH.sub.2                                                                         2.5                                          Ibuprofen   CH.sub.3                                                                             CH.sub.3      8.6                                                      CH.sub.3                                                                             CH.sub.2 CONH.sub.2                                                                         9.6                                                      CH.sub.3                                                                              ##STR36##    10.8                                         Ketoprofen  CH.sub.3                                                                             CH.sub.3      1.1                                                      C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                             0.5                                                      CH.sub.3                                                                             CH.sub.2 CONH.sub.2                                                                         2.3                                          Flurbiprofen                                                                              CH.sub.3                                                                             CH.sub.3      10.8                                                     C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                             4.7                                          Fenbufen    CH.sub.3                                                                             CH.sub.3      9.2                                                      C.sub.2 H.sub.5                                                                      C.sub. 2 H.sub.5                                                                            3.8                                          Indomethacin                                                                              CH.sub.3                                                                             CH.sub.3      130                                                      C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                             25                                                       CH.sub.3                                                                             CH.sub.2 CH.sub.2 OH                                                                        140                                                      CH.sub.2 CH.sub.2 OH                                                                 CH.sub.2 CH.sub.2 OH                                                                        88                                           Sulindac    C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                             26                                           Tolmetin    CH.sub.3                                                                             CH.sub.3      14.6                                                     C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                             13.4                                         Tolfenamic acid                                                                           CH.sub.3                                                                             CH.sub.3      2.8                                                      C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                             5.0                                                      C.sub.2 H.sub.5                                                                      CH.sub.2 CH.sub.2 OH                                                                        3.0                                          4-Aminobenzoic acid                                                                       C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                             0.6                                          Tranexamic acid                                                                           CH.sub.3                                                                             CH.sub.3      1.2                                          L-Phenylalanine                                                                           C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                             0.2                                          L-Tyrosine  C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                             0.5                                          4-Hydroxybenzoic acid                                                                     C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                             1.8                                          Salicylic acid                                                                            CH.sub.3                                                                             CH.sub.3      0.08                                                     C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                             0.08                                                     CH.sub.3                                                                             CH.sub.2 CONH.sub.2                                                                         0.33                                                      ##STR37##           22                                           Mefenamic acid                                                                            CH.sub.3                                                                             CH.sub. 3     2.4                                          Diflunisal  C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                             79                                           4-Biphenylacetic acid                                                                     CH.sub.3                                                                             CH.sub.2 CONH.sub.2                                                                         2.1                                          __________________________________________________________________________

                  TABLE 5                                                         ______________________________________                                        Half-lives (t.sub.1/2) of hydrolysis of esters of various drugs               containing a carboxylic acid function in 80% human plasma.sup.a                            t.sub.1/2                                                                       Methyl      N,N-diethylglycol-                                 Acid           ester       amide ester                                        ______________________________________                                        Salicylic acid 17.6    h       0.08   min                                     Benzoic acid   2.0     h       0.04   min                                     Naproxen       20.1    h.sup.b 0.6    min                                     Ketoprofen     >20     h       0.5    min                                     Fenbufen       4.7     h       3.8    min                                     Tolmetin       19      h       13.4   min                                     Tolfenamic acid                                                                              100     h       5.0    min                                     Indomethacin   150     h       25     min                                     L-Phenylalanine                                                                              29      min     0.2    min                                     4-Hydroxybenzoic acid                                                                        >50     h       1.8    min                                     4-Aminobenzoic acid                                                                          >100    h.sup.b 0.6    min                                     Tranexamic acid                                                                              >3      h       1.2    min.sup.c                               L-Tyrosine     59      min.sup.b                                                                             0.5    min                                     ______________________________________                                         .sup.a At pH 7.4 and 37° C.                                            .sup.b Value for ethyl ester                                                  .sup.c Value for N,Ndimethylglycolamide ester                            

                  TABLE 6                                                         ______________________________________                                        Plasma concentrations of naproxen following oral admini-                      stration of naproxen (4.8 mg/kg) or the equivalent amount of                  the N,N-(β-hydroxyethyl)glycolamide ester of naproxen to                 rabbits.                                                                                    Naproxen plasma conc.                                           Time after    (μg/ml)                                                      administration                                                                              After naproxen                                                                            After ester                                         (min)         administration                                                                            administration                                      ______________________________________                                         10           2.8         2.7                                                  25           5.1         5.7                                                  50           6.4         8.3                                                  75           7.1         8.2                                                 100           7.4         7.7                                                 125           7.1         6.7                                                 200           5.4         4.0                                                 300           3.6         3.6                                                 400           2.7         3.3                                                 450           2.4         3.2                                                 ______________________________________                                    

REFERENCES CITED

Boltze, K.-H. & H. Kreisfeld (1977): Arzneim.-Forsche. 27, 1,300-1,312.

Todd, P.A. & R.C. Heel (1986): Drugs 31, 198-248.

Concilio, C. & A. Bongini (1966): Ann. Chim. (Rome) 56, 417-426.

Hankins, E.M. (1965): U.S. Pat. No. 3,173,900.

Speziale, A.J. & P.C. Hamm (1956): J. Am. Chem. Soc. 78, 2,556-2,559.

Berkelhammer, G., S. DuBreuil & R.W. Young (1961): J. Org. Chem. 26,2,281-2,288.

Weaver, W.E. & W.M. Whaley (1947): J. Am. Chem. Soc. 69, 515-516.

Ronwin, E. (1953): J. Org. Chem. 18, 127-132.

Holysz, R.P. & H.E. Stavely (1950): J. Am. Chem. Soc. 72, 4,760-4,763.

Ferres, H. (1983): Drugs of Today 19, 499-538.

Harrison, I.T., B. Lewis, P. Nelson, W. Rooks, A. Roszkowski, A.Tomolonis & J. Fried (1970): J. Med. Chem. 13, 203-205.

Child, R.G., A.C. Osterberg, A.E. Sloboda & A.S. Tomcufcik (1977): J.Pharm. Sci., 66, 466-476.

Tocco, D.J., F.A. de Luna, A.E.W. Duncan, T.C. Vassil & E.H. Ulm (1982):Drug Metab. Disp. 10, 15-19.

Larmour, I., B. Jackson, R. Cubela & C.I. Johnston (1985): Br. J. CIin.PharmacoI. 19, 701-704.

Rakhit, A. & V. Tipnis (1984): Clin. Chem 30, 1,237-1,239.

Tipnis, V. & A. Rakhit (1985): J. Chromatogr. 345, 396-401.

Boltze, K.-H., O. Brendler, H. Jacobi, W. Opitz, S. Raddatz, P.-R.Seidel & D. Vollbrecht (1980): Arzneim.-Forsch. 30, 1,314-1,325.

"Remington's Pharmaceutical Sciences", Sixteenth Edition (1980), MackPublishing Company, Easton, U.S.A.

Marvel, C.S., J.R. Elliott, F.E. Boeltner & H. Yaska (1946): J. Am.Chem. Soc. 68, 1,681-1,686.

We claim:
 1. Compounds of the formula I ##STR38## wherein R--COO--represents the acyloxy residue of a carboxylic acid drug or medicamentselected from:Indomethacin Naproxen Ibuprofen Flurbiprofen5-Aminosalicylic Acid L-Dopa Furosemide and N-Acetylcysteineand R₁ andR₂ are the same or different and are selected from a group consisting ofan alkyl group, an alkenyl group, an aryl group, an aralkyl group, acycloalkyl group, in which the alkyl, alkenyl, aryl, aralkyl orcycloalkyl group is unsubstituted or substituted with one or moresubstituents selected from: a halogen atom, a hydroxy group, a straightor branched-chain alkoxy group having the formula R₃ --O--, wherein R₃represents an alkyl group or an aryl group, which groups may beunsubstituted or substituted with one or more of a halogen atom or ahydroxy group, a carbamoyl group having the formula ##STR39## wherein R₄and R₅ are the same or different and are hydrogen, an alkyl group or areselected from a group having the formula --CH₂ NR₇ R₆, wherein R₆ and R₇are the same or different and are hydrogen, or an alkyl group, an aminogroup having the formula --NR₈ R₉, wherein R₈ and R₉ are the same ordifferent and are hydrogen, or an alkyl group an acyloxy group havingthe formula --COOR₁₀, wherein R₁₀ is an alkyl, aryl or aralkyl group, anoxyacyl group having the formula R₁₁ COO-- wherein R₁₁ is hydrogen, analkyl group, an aryl group, an aralkyl group, a cycloalkyl group, inwhich the alkyl, aryl, aralkyl or cycloalkyl group is unsubstituted orsubstituted with one or more of a halogen atom, a hydroxy group, analkoxy group of the formula R₃ --O-- as defined above, a carbamoyl groupof the formula --CONR₄ R₅ as defined above or an amino group having theformula --NR₈ R₉ as defined above;and nontoxic pharmaceuticallyacceptable acid addition salts thereof.
 2. Compounds according to claim1 wherein R₁ is methyl or ethyl, and KR₂ is selected from--CH₃ --CH₂ CH₃--CH₂ CH₂ OH --CH₂ CONH₂ --CH₂ CH₂ CONH₂ --CH₂ CH₂ OOCCH₂ N(CH₃)₂ --CH₂CH₂ OOCCH₂ N(C₂ H₅)₂ --CH₂ CH₂ OOCCH₂ NH₂ --CH₂ CONHCH₂ N(CH₃)₂ --CH₂CONHCH₂ N(C₂ H₅)₂ --CH₂ CH₂ N(CH₃)₂ --CH₂ CONHCH₂ NH₂ --CH₂ CONH--CH₃.3. Compounds of the formula I ##STR40## wherein R₁ and R₂ both are alkylor both are --CH₂ CH₂ OH and R--COO is the acyloxy residue of acarboxylic acid drug selected from:Indomethacin Naproxen IbuprofenFlurbiprofen 5-Aminosalicylic acid L-Dopa Furosemide andN-Acetylcysteine.
 4. Compounds according to claim 1, wherein R--COO isderived from Naproxen.
 5. Compounds according to claim 3, wherein R--COOis derived from Naproxen.
 6. Compounds according to claim 1, whereinR--COO is derived from L-Dopa or N-acetylcysteine.
 7. Compoundsaccording to claim 3, wherein R--COO is derived from L-Dopa orN-acetylcysteine.
 8. A pharmaceutical composition comprising apharmaceutically acceptable excipient and a pharmaceutically effectiveamount of a compound according to any one of claims 1-7.